Concomitant PIK3CD and TNFRSF9 deficiencies cause chronic active Epstein-Barr virus infection of T cells

Abstract

Infection of T cells by Epstein-Barr virus (EBV) causes chronic active EBV infection (CAEBV) characterized by T cell lymphoproliferative disorders (T-LPD) of unclear etiology. Here, we identified two homozygous biallelic loss-of-function mutations in PIK3CD and TNFRSF9 in a patient who developed a fatal CAEBV. The mutation in TNFRSF9 gene coding CD137/4-1BB, a costimulatory molecule expressed by antigen-specific activated T cells, resulted in a complete loss of CD137 expression and impaired T cell expansion toward CD137 ligand–expressing cells. Isolated as observed in one sibling, CD137 deficiency resulted in persistent EBV-infected T cells but without clinical manifestations. The mutation in PIK3CD gene that encodes the catalytic subunit p110δ of the PI3K significantly reduced its kinase activity. Deficient T cells for PIK3CD exhibited reduced AKT signaling, while calcium flux, RAS-MAPK activation, and proliferation were increased, suggestive of an imbalance between the PLCγ1 and PI3K pathways. These skewed signals in T cells may sustain accumulation of EBV-infected T cells, a process controlled by the CD137–CD137L pathway, highlighting its critical role in immunity to EBV.

CD70 Deficiency Associated With Chronic Epstein-Barr Virus Infection, Recurrent Airway Infections and Severe Gingivitis in a 24-Year-Old Woman

“…Therefore, the signal induced by half of CD70 receptors on the surface of LCL seems sufficient to maintain an efficient immune response to EBV. It is likely, that other receptors from the TNFR superfamily, like CD137/CD137L, deliver EBV-specific T cell cosignals required for their expansion (21).…”

Destroy, what destroys you

“…9 This phenotype was also observed in the two patients analyzed by Rodriguez et al, where memory B cell numbers were severely reduced. 10 Although B cell subsets were not analyzed by Alosaimi et al, low IgG and high IgM levels, and a poor antibody response to tetanus toxoid and an absent recall response to pneumococcal polysaccharide vaccine, in one of the two patients indicate a disturbance in B cell maturation. Somekh et al also analyzed Tfh numbers and found reduced counts in 3 of the 4 patients.…”

“…The authors conclude that the lack of CD137 costimulation prevented the clearance of EBV-infected T cells. 10 Two of the four patients analyzed by Somekh et al suffered from an EBV-related B cell lymphoma, Hodgkin's lymphoma (HL) and Burkitt's lymphoma, respectively, and one patient described by Alosaimi et al presented with HL. 8,9 One patient analyzed by Rodriguez et al suffered from EBV-associated T cell lymphoproliferative disease, and finally succumbed to hemophagocytic lymphohistiocytosis (HLH).…”

“…8,9 One patient analyzed by Rodriguez et al suffered from EBV-associated T cell lymphoproliferative disease, and finally succumbed to hemophagocytic lymphohistiocytosis (HLH). 10 Thus, a common denominator of the three studies is that mutations in CD137 facilitate EBV-associated diseases, implying that under normal conditions CD137 limits EBV in causing pathology. This notion is supported by the diminished cytotoxic T cell response against EBV-infected B cells in the two patients analyzed by Alosaimi et al 8 The 8 patients were inflicted by infections from a range of different pathogens which varied among the patients.…”

4-1BB (CD137) in anticancer chimeras

“…The only relevant natural ligand so far discovered is 4-1BBL, which forms trimers on the membrane of mature macrophages, dendritic cells, and activated B cells (Croft et al, 2013). The key role of 4-1BB costimulation in CTL biology is best perceived considering the phenotype of CD137 −/− mice upon viral infection (Wortzman et al, 2013) and the alterations in the control of herpes viruses such as Epstein-Barr in patients with homozygous CD137 mutations (Rodriguez et al, 2019). Simple experiments in transplantable tumor models indicated that rejection of established tumors can be elicited by systemic administration of agonist anti-4-1BB mAb (Melero et al, 1997).…”